Cardiac manifestations of HIV

1

How have the cardiac manifestations of human immunodeficiency virus changed over the years?

• Until the early 1990s, cardiac manifestations of human immunodeficiency virus (HIV) and associated acquired immunodeficiency syndrome (AIDS) frequently included overt and often acute viral and inflammatory presentations, such as pericardial disease, myocarditis, dilated and infiltrative cardiomyopathies, pulmonary hypertension, arrhythmias, and endocarditis. As continuous, uninterrupted antiretroviral therapy (ART) as soon as possible after HIV diagnosis has become standard of care, HIV has transformed from a fatal infection to a chronically managed disease, and HIV-infected patients are now facing the challenges of chronic diseases, including cardiovascular disease (CVD). When compared with the general population, patients with HIV are at increased risk of CVDs ranging from myocardial infarction (MI) to heart failure (HF), and CVs may occur earlier and progress more rapidly.

• HIV patients have a higher prevalence of traditional CVD risk factors—especially smoking—although elevated risks for MI and HF among people with HIV remain after adjustment for traditional risk factors. Historically, much of this excess risk was attributed to ART, although continuous (vs. interrupted) ART was actually found to decrease MI risk in a large randomized trial. Given associations of HIV viral load and immune suppression with inflammation and CVD, as well as several mechanistic studies, the primary driver of HIV-associated increased CVD risk is now largely thought to be chronic immune activation and inflammation.

2

What are HIV-related cardiac complications?

• In the early- and pre-ART eras (early 2000s and prior), common CVD manifestations of HIV/AIDS included:

• Pericardial effusion/tamponade.

• Dilated cardiomyopathy and severe systolic dysfunction.

• Myocarditis.

• Marantic (thrombotic) or infectious endocarditis.

• Cardiac tumors (Kaposi’s sarcoma, lymphoma).

• Pulmonary arterial hypertension (PAH).

• Sudden cardiac death.

  • These complications may still occur in the present era, especially in the setting of poor HIV control, although now common CVD complications tend to be more subacute and chronic, including:

• Coronary artery disease and MI.

• HF with preserved and reduced ejection fraction.

• Sudden cardiac death.

  • A summary of HIV-associated cardiovascular complications is given in Table 46.1 .

    Table 46.1

    Summary of HIV-Associated Cardiovascular Diseases

    Adapted from Fisher, S. D., & Lipschultz, S. E. (2015). Cardiovascular abnormalities in HIV-infected individuals. In D. L. Mann, D. P. Zipes, P. Libby, R. O. Bonow, & E. Braunwald (Eds.), Braunwald’s heart disease: a textbook of cardiovascular medicine . Philadelphia: Elsevier Saunders.

    DISEASE	POSSIBLE CAUSES	TREATMENT
    Accelerated atherosclerosis	Atherogenesis with virus-infected macrophages, chronic immune activation and inflammation, glucose intolerance, dyslipidemia, endothelial dysfunction	Smoking cessation, low-fat diet, aerobic exercise, blood pressure control, guideline-based statin use, percutaneous coronary intervention, coronary artery bypass surgery
    Left ventricular systolic dysfunction	CAD, drug related (AZT, IL-2, doxorubicin, interferon), infectious, cytokines, autoimmune	Standard heart failure therapies, treatment of infection, nutritional replacement, IVIG, intensify antiretroviral therapy
    Left ventricular diastolic dysfunction	Metabolic disturbances, TNF, IL-6, hypertension, chronic viral infection	Treat hypertension, intensify antiretroviral therapy
    Right ventricular dysfunction	Recurrent pulmonary infections, pulmonary arteritis/arterial hypertension, microvascular pulmonary emboli, COPD	Diuretics, treat underlying lung infection or disease, anticoagulation as clinically indicated
    Arrhythmias	Drug therapy, pentamidine, autonomic dysfunction, acidosis, electrolyte abnormalities	Discontinue drug, electrolyte replacement
    Pericardial	Bacterial, viral, other pathogens, malignancy, uremia	Treat underlying cause, intensify antiretroviral therapy, serial echocardiograms, pericardiocentesis or window
    Endocarditis	Nonbacterial thrombotic, autoimmune, bacterial, fungal	Intravenous antibiotics, valve replacement

    AZT , Azidothymidine; CAD , coronary artery disease; COPD, chronic obstructive pulmonary disease; IL , interleukin; IVIG, intravenous immunoglobulin; TNF , tumor necrosis factor.

3

What are the incidence and pathophysiology of HIV-associated myocarditis and AIDS cardiomyopathy?

• In different series, one-third to one-half of patients in the pre-ART era (or where ART therapy was not available) dying of AIDS had lymphocytic infiltration at autopsy. Eighty percent of these patients had no other pathogens identified. Additionally, up to 10% of endomyocardial specimens in HIV patients have evidence of other infections (Coxsackie B, Epstein-Barr virus, adenovirus, cytomegalovirus). Studies have demonstrated the role of computed tomography (CT) and magnetic resonance imaging (MRI) to noninvasively identify myocarditis of all etiologies, which can be applied to the HIV population.

• The initiation of ART therapy has significantly reduced the incidence of cardiomyopathy, likely due to both reduction in HIV itself and reduction in the presence of opportunistic infections.

• HIV is thought to cause myocarditis from direct action of HIV on myocytes or indirectly through toxins. Patients with HIV and cardiomyopathy have a worse prognosis than those with cardiomyopathy due to other causes of cardiomyopathy. HF caused by HIV-associated left ventricular dysfunction is most commonly found in patients with the lowest CD4 counts and is a marker of poor prognosis.

4

What are the risks for heart failure among people with HIV on antiretroviral therapy and with viral suppression?

• Even in the modern ART era—with widespread availability and uptake of ART—risks for HF are elevated among people with HIV. Studies using different definitions of HF (administrative code-based vs. physician-adjudicated) in different cohorts to investigate HF risks for people with HIV in the modern ART era demonstrated 1.3- to 2.1-fold increased risks for HF among people with HIV compared with controls, after adjustment for demographics and traditional CVD risk factors. As might be expected, the lower the CD4 count (more advanced immunosuppression), CD4/CD8 ratio (a marker of immune biasing toward more proinflammatory responses), and the higher the HIV viral load, the higher the risk for HF.

5

Do people with HIV have elevated risks for heart failure with reduced and preserved ejection fraction (HFrEF and HFpEF) and, if so, why?

• People with HIV have increased risks of HFrEF and HFpEF compared with people without HIV. Certainly, acute and severe systolic dysfunction with lymphocytic infiltrates still occur among people with poor HIV control and advanced immunosuppression. Nevertheless, perhaps the most common etiologies of HF among people with HIV relate to chronic noncommunicable disease processes, likely accelerated by chronic immune activation and inflammation, although there are a number of potential reasons for elevated HF among people with HIV. Metabolic disturbances among people with HIV, coupled with arteriosclerosis and microvascular dysfunction, are likely major causes of HFpEF and, particularly in the setting of prior MI, HFrEF. Propensity toward myocardial fibrosis/scar in HIV may play a role. Several studies of people without known heart disease demonstrated that people with HIV have more myocardial fibrosis than controls without HIV. Furthermore, after MI, people with HIV have more myocardial scar and lower left ventricular ejection fraction (LVEF) than people without HIV. Defining the immunologic, inflammatory, and other factors underlying this propensity for myocardial damage in HIV is a high-priority research area.